Acute Myelogenous Leukemia
Conditions
Keywords
acute myelogenous leukemia
Brief summary
This is a phase II trial designed to test the safety and efficacy (disease free survival \[DFS\]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML). The natural killer (NK) cell product will be given to patients 60 years and older who are in a first complete remission after 1 or 2 courses of standard AML induction. After a preparative regimen of cyclophosphamide and fludarabine, patients will receive a single infusion of either CD3-/CD19- NK cells or CD3-/CD56+ NK cells followed by a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion.
Detailed description
The trial will use a single-stage design and will take place in two parts. The first part will support the selection of the better NK cell product as measured by in vivo NK cell expansion. Successful in vivo NK cell expansion is defined as 40% donor DNA and 40% of lymphocytes are NK cells at day 7 post infusion OR 20% donor DNA and 20% of lymphocytes are NK cells at day 14 post infusion. Part 1: 1:1 randomization with 10 patients per cohort to either: 1. CD3-/CD19- NK cell product or 2. CD3-/CD56+ purified NK cell product The product with better NK cell expansion will be used for the rest of the trial. If the results and safety profile are equivalent, the CD56+ selection approach will be used. If neither approach results in successful NK cell expansion, the trial will be stopped and the platform redesigned. Part 2: complete the trial by enrolling an additional 26 patients using the product deemed successful during part 1 to estimate the primary endpoint (DFS at 12 months)
Interventions
BIOLOGICALCD3-/CD19- natural killer cells
Infused on Day 0. The final CD3-/CD19- product must contain at least 20% NK cells based on previous studies using this cell product processing technique. The entire cell product will be administered except in cases where the T cell count exceeds the T cell infusion threshold. In such situations, the product volume will be adjusted to meet the lot release criteria.
BIOLOGICALCD3-CD56+ natural killer cells
Infused on Day 0. The final CD3-/CD56+ product must contain at least 70% NK cells based on a previous study using this cell product processing technique. The entire cell product will be administered except in cases where the T cell count exceeds the T cell infusion threshold. In such situations, the product volume will be adjusted to meet the lot release criteria.
DEVICECliniMACS® CD3 and CD19 Reagent System
In combination used to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19-). The entire cell product will be administered except in cases where the T cell count exceeds the T cell infusion threshold. In such situations, the product volume will be adjusted to meet the lot release criteria.
DEVICECliniMACS® CD56 Reagent System
CliniMACS® CD3 and CD19 Reagent System will be used in addition to CliniMACS® CD56 Reagent System to enrich CD56+ NK cells. The entire cell product will be administered except in cases where the T cell count exceeds the T cell infusion threshold. In such situations, the product volume will be adjusted to meet the lot release criteria.
DRUGCyclophosphamide
Infused intravenously 60 mg/kg x day -5
DRUGFludarabine
Fludarabine 25 mg/m2 x days -6 through -2
DRUGAldesleukin
IL-2 subcutaneously at 6 million units every other day for 6 doses - begin evening of the NK cell infusion.
Sponsors
Miltenyi Biomedicine GmbH
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of acute myelogenous leukemia (except acute promyelocytic leukemia) in a first complete remission (CR1) and meet the following criteria: * Meets the definition of complete remission by morphologic criteria including \<5% blasts in a moderately cellular (\> 20% cellularity) or cellular marrow. * Complete remission (CR) was achieved after no more than 2 cycles of standard induction chemotherapy. Early re-induction therapy based on residual disease on a day 14 bone marrow (BM) will count as a 2nd cycle. Prior therapy with demethylating agents (i.e. azacitidine) is allowed, but patients must have attained CR after standard cytotoxic therapy (defined as absolute neutrophil count (ANC) \> 1000 cells/μL, platelets \> 100 x 10\^9/L) * No more than 3 months have lapsed from attainment of CR1 * No acute myelogenous leukemia (AML) consolidation therapy administered prior to enrollment * Not a candidate for allogeneic stem cell transplantation * ≥ 60 years of age * Karnofsky performance status ≥ 70% * Available related HLA haploidentical natural killer (NK) cell donor (sibling, offspring, or offspring of an HLA identical sibling) by at least Class I serologic typing at the A&B locus (donor age 18-75 years) * At least 30 days since last dose of chemotherapy * Adequate organ function within 14 days of enrollment defined as: * Creatinine: ≤ 2.0 mg/dL * Hepatic: aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) \< 5 x upper limit of institutional normal (ULN) * Pulmonary: oxygen saturation ≥ 90% on room air * Cardiac: left ventricular ejection fraction (LVEF) by echocardiogram (ECHO or MUGA) ≥ 40%, no uncontrolled angina, uncontrolled atrial or ventricular arrhythmias, or evidence of acute ischemia or active conduction system abnormalities (rate controlled a-fib is not an exclusion) * Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the NK cell infusion (excluding preparative regimen pre-meds) * Voluntary written consent
Exclusion criteria
* Biphenotypic acute leukemia * New progressive pulmonary infiltrates on screening chest x-ray or chest Computed Tomography scan that has not been evaluated with bronchoscopy (when feasible). Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections). * Uncontrolled bacterial, fungal, or viral infections including human immunodeficiency virus (HIV) - chronic asymptomatic viral hepatitis is allowed * Pleural effusion large enough to be detectable on chest x-ray * Known hypersensitivity to one or more of the study agents Donor Selection: * Related donor (sibling, offspring, or offspring of an HLA identical sibling) 18-75 years of age * At least 40 kilograms * In general good health as determined by the medical provider * Negative for hepatitis and HIV on donor viral screen * HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus * Not pregnant * Voluntary written consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival | 1 Year | the length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Chronic Graft-Versus-Host Disease (GVHD) | 1 Year | Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host. |
| Incidence of Acute Graft-Versus-Host Disease (GVHD) | Day 100 | Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. |
| Incidence of Infusional Toxicities | Day 100 | Patients will be monitored for adverse effects of the NK cell infusion such as rash, acute allergic reaction, bronchospasm, respiratory distress, and acute vascular leak syndrome. |
| Overall Survival | 1 Year and 2 Years | The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. |
| Disease-Free Survival | 2 Years | the length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. |
| Treatment-Related Mortality | Day 100, 1 Year and 2 Years | In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation. |
Countries
United States
Outcome results
None listed